The comorbidity of anxiety disorders with bipolar disorder is a rule, not an exception, with a negative impact on both course and treatment outcome. So far, there are no guidelines or consensus for the treatment of this comorbidity. There are also no efficacy data that support the use of antidepressants or benzodiazepines in the treatment of anxiety disorder in this population. Benzodiazepines, the second-line agents for some primary anxiety disorders, may be riskier for patients with bipolar disorder because they are associated with a high rate of comorbid substance use disorder. Some preliminary data have shown that antipsychotics, especially atypical anti- psychotics, may be a viable alternative for patients with comorbid bipolar and anxiety disorders with or without substance use disorder.

COMORBIDITY Incidence

Data from the National Comorbidity Survey have shown that patients with bipolar I disorder (BPI) had high rates of lifetime Axis I comorbidity and that anxiety disorder and substance use disorder were the 2 most common comorbid conditions with BPI.1 Of the 59 patients with BPI, 93% had at least one anxiety disorder and 61% had at least one substance use disorder.

More recently, the findings from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) have shown that patients with BPI (n = 1411) had high rates of comorbid anxiety disorders with specific phobia (30%), panic disorder with/ without agoraphobia (26%), generalized anxiety disorder (GAD) (25%), and social phobia (24%).2 Bauer and colleagues3 have reported that in clinical outpatient samples, the lifetime rates of anxiety disorder ranged from 24% to 53% with BPI and 16% to 46% with bipolar II disorder (BPII).3 Data from a cohort of patients with rapid cycling BPI or BPII (n = 566) have shown that 35% of patients had lifetime GAD, 27% had panic disorder, and 7% had obsessive-compulsive disorder (OCD).4

Comorbid substance use disorder with bipolar disorder is also a rule, not an exception. In the Epidemiologic Catchment Area study, patients with BPI or BPII had the highest rates of substance use disorder among all patients with mental illness, with a lifetime incidence of alcohol use disorder of 44% and a lifetime incidence of drug use disorder of 34%.5 In the NESARC, more than half of the patients with BPI (58%) had a lifetime history of alcohol use disorder, and more than one third (37.5%) had a lifetime history of drug use disorder.2 In clinical outpatient studies, the rates of lifetime comorbid substance use disorder with bipolar disorder were 42% to 61% with BPI and 31% to 48% with BPII.6-8

Although the exact rates of double or multiple comorbidities of anxiety disorders and substance use disorders in bipolar disorder are unknown, high rates of these comorbidities in bipolar disorder have been observed in various study populations. These include national surveys,1,2 a bipolar research network or program,7,9 a Veterans Affairs cooperative study,3 and our research center.4 In our sample, at least 31% of patients with rapid cycling bipolar disorder had both comorbid anxiety disorder and substance use disorder.

Impact

Comorbid anxiety disorder has a significantly negative impact on the quality of life of patients who have bipolar disorder, as manifested by earlier onset of illness,10-12 more rapid cycling, suicidal behavior, substance use disorder,9,11-14 poorer response to lithium or anticonvulsants,14-16 and worse prognosis.14,15,17,18 The data from a study of patients with rapid cycling bipolar disorder have shown that comorbid anxiety disorder and/or substance use disorder was associated with an increased risk of hospitalization or suicide attempt(s).19

Treatment issues

Findings from the Systematic Treatment Enhancement Program-Bipolar Disorder (STEP-BP) have shown that comorbid anxiety and bipolar disorders were usually undertreated, although antidepressants were more commonly prescribed for patients with the comorbidity.20 More recently, data from the STEP-BP have shown that a current anxiety diagnosis at study entry was associated with the increased risk of depression recurrence; the proportion of days with anxiety in the previous year was an independent predictor for depression recurrence.21 However, it is still unclear whether adequate treatment of anxiety disorders will change the course and treatment outcome in patients with bipolar disorder.

Although newer antidepressants, especially SSRIs, have proved efficacious in the treatment of primary anxiety disorders and have commonly been prescribed for patients with bipolar disorder,20 there are no data to support their use in treating anxiety in bipolar disorder. The issue of antidepressant-induced mania remains controversial22 although there is evidence that antidepressants may trigger mania or destabilize the course of the bipolar disorder, especially without the concomitant use of a mood stabilizer.17,23-25

In a 6-year follow-up study of patients with schizophrenia or bipolar and substance use disorders, treatment with a benzodiazepine was not associated with any of the measured outcomes other than increasing the likelihood of benzodiazepine abuse—15% in the treatment group versus 6% in the nontreatment group.26 Clearly, benzodiazepines for anxiety disorder should be used with caution in patients who have bipolar disorder and a substance use disorder.